Project 1 will draw upon empirical and theoretical tools to address a central component of the Center hypothesis: that disturbances of dopamine (DA) in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia contribute in specific ways to the cognitive deficits observed in this illness. Studies will build on previous work establishing that patients with schizophrenia demonstrate a selective deficit in the ability to actively maintain and use context information to appropriately guide behavior. We have hypothesized that this deficit arises from a disturbance of DA activity in DLPFC. Although we have generated behavioral evidence in support of this hypothesis, we have not yet established its relationship to deficits of either DLPFC or DA function. The primary focus of this project will be to establish this relationship, which will provide a direct conceptual bridge between the neurobiological mechanisms involved in schizophrenia and their behavioral manifestations. Under Specific Aim 1 we will conduct functional MRI studies of patients with schizophrenia, to examine the relationship between DLPFC function and performance on cognitive tasks that rely on the processing of context. These studies will be conducted in the same subject populations as those used to study eye movement control and morphometry in Project-Sweeney. Furthermore, they will use the same task that will be used in electrophysiological studies of monkey prefrontal cortex in Project-Olson, thus providing more detailed information about the physiological function of regions engaged by task performance. Under Specific Aim 2, we will examine the influence that pharmacological manipulations of DA function have on behavioral performance, providing information about the role of DA in the processing of context,, and a link to studies of the influence of DA on PFC function to be conducted in Project-Zigmond. Under Specific Aim 3, we will construct computational models of DLPFC and FA function that will be used to interpret the anatomical and physiological data generated about these systems in Projects with regard to their influence on the behavioral functions to be studied in our project and Project-Sweeney. Together, these studies should provide critical new information about the relationship between the neural mechanisms that are impaired in schizophrenia, and their impact on behavior in this illness.